Process for the preparation of a 2-pyridylethylcarboxamide derivative

ABSTRACT

Process for the preparation of a N-[2-(2-pyridinyl)ethyl]carboxamide derivative of general formula (I) or a salt thereof 
                         
Intermediate of general formula (II)
 
                         
Intermediate of general formula (III).

CROSS REFERENCE TO RELATED APPLICATION(S)

The present application is a 35 U.S.C. §371 national phase conversion ofPCT/EP2005/056895 filed Dec. 19, 2005, which claims priority of EuropeanApplication No. 04356203.2 filed Dec. 21, 2004.

The present invention relates to a novel process for the preparation ofN-[2-(2-pyridinyl)ethyl]carboxamide derivative which is useful aspesticide compound, starting with a halogenobenzoyl derivative toproduce a N-acetoxymethylcarboxamide derivative and then coupling itwith a 2-pyridyl acetate derivative.

Patent application WO 2004/016088 discloses the preparation ofN-[2-(2-pyridinyl)ethyl]benzamide derivatives starting from2-halogenopyridine derivatives to produce 2-ethylaminopyridinederivatives and then coupling these 2-ethylaminopyridine derivativeswith a halogenobenzoyl derivative.

The process disclosed in this patent application presents the drawbackin that one of the step of this process consists in the reduction of a2-methylcyanopyridine derivative to produce a 2-ethylaminopyridinederivative. Such a step is difficult and its yield is not acceptable atan industrial scale.

We have now found an alternative method to prepareN-[2-(2-pyridinyl)ethyl]carboxamide derivative which overcomes theseproblems and which is applicable to industrial scale operation.

Accordingly, the present invention relates to a process for thepreparation of a N-[2-(2-pyridinyl)ethyl]carboxamide derivative ofgeneral formula (I) or a salt thereof

in which:

-   -   p is an integer equal to 1, 2, 3 or 4;    -   X is the same or different and is a hydrogen atom, a halogen        atom, a nitro group, a cyano group, a hydroxy group, an amino        group, a sulfanyl group, a pentafluoro-λ⁶-sulfanyl group, a        formyl group, a formyloxy group, a formylamino group, a carboxy        group, a carbamoyl group, a N-hydroxycarbamoyl group, a        carbamate group, a (hydroxyimino)-C₁-C₆-alkyl group, a        C₁-C₈-alkyl, a C₁-C₈-halogenoalkyl having 1 to 5 halogen atoms,        a C₂-C₈-alkenyl, a C₂-C₈-alkynyl, a C₁-C₈-alkylamino, a        di-C₁-C₈-alkylamino, a C₁-C₈-alkoxy, a C₁-C₈-halogenoalkoxy        having 1 to 5 halogen atoms, a C₁-C₈-alkylsulfanyl, a        C₁-C₈-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a        C₂-C₈-alkenyloxy, a C₂-C₈-halogenoalkenyloxy having 1 to 5        halogen atoms, a C₃-C₈-alkynyloxy, a C₃-C₈-halogenoalkynyloxy        having 1 to 5 halogen atoms, a C₃-C₈-cycloalkyl, a        C₃-C₈-halogenocycloalkyl having 1 to 5 halogen atoms, a        C₁-C₈-alkylcarbonyl, a C₁-C₈-halogenoalkylcarbonyl having 1 to 5        halogen atoms, a C₁-C₈-alkylcarbamoyl, a        di-C₁-C₈-alkylcarbamoyl, a (N—C₁-C₈-alkyl)oxycarbamoyl, a        C₁-C₈-alkoxycarbamoyl, a (N—C₁-C₈-alkyl)-C₁-C₈-alkoxycarbamoyl,        a C₁-C₈-alkoxycarbonyl, a C₁-C₈-halogenoalkoxycarbonyl having 1        to 5 halogen atoms, a C₁-C₈-alkylcarbonyloxy, a        C₁-C₈-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a        C₁-C₈-alkylcarbonylamino, a C₁-C₈-halogenoalkylcarbonylamino        having 1 to 5 halogen atoms, a C₁-C₈-alkylaminocarbonyloxy, a        di-C₁-C₈-alkylaminocarbonyloxy, a C₁-C₈-alkyloxycarbonyloxy, a        C₁-C₈-alkylsulphenyl, a C₁-C₈-halogenoalkylsulphenyl having 1 to        5 halogen atoms, a C₁-C₈-alkylsulphinyl, a        C₁-C₈-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a        C₁-C₈-alkylsulphonyl, a C₁-C₈-halogenoalkyl-sulphonyl having 1        to 5 halogen atoms, a (C₁-C₆-alkoxyimino)-C₁-C₆-alkyl, a        (C₁-C₆-alkenyloxyimino)-C₁-C₆-alkyl, a        (C₁-C₆-alkynyloxyimino)-C₁-C₆-alkyl, a        (benzyloxyimino)-C₁-C₆-alkyl, a benzyloxy, a benzylsulfanyl, a        benzylamino, a phenoxy, a phenylsulfanyl or a phenylamino;    -   R¹ is a hydrogen atom, a C₁-C₈-alkyl, a C₁-C₈-halogenoalkyl        having 1 to 5 halogen atoms or a C₁-C₈-alkoxycarbonyl;    -   R² is a hydrogen atom or a cyclopropyl group; and    -   A represents a phenyl group or a 5-, 6- or 7-membered non-fused        heterocycle with one, two or three heteroatoms which may be the        same or different, the heterocycle being linked by a carbon        atom; each of this group being optionally substituted by one or        more substituents chosen independently of each other as being a        halogen atom, a nitro group, a cyano group, a hydroxy group, an        amino group, a sulfanyl group, a pentafluoro-λ⁶-sulfanyl group,        a formyl group, a formyloxy group, a formylamino group, a        carboxy group, a C₁-C₈-alkyl, a C₁-C₈-halogenoalkyl having 1 to        5 halogen atoms, a C₂-C₈-alkenyl, a C₂-C₈-alkynyl, a        C₁-C₈-alkylamino, a di-C₁-C₈-alkylamino, a C₁-C₈-alkoxy, a        C₁-C₈-halogenoalkoxy having 1 to 5 halogen atoms, a        C₁-C₈-alkoxy-C₂-C₈-alkenyl, a C₁-C₈-alkylsulfanyl, a        C₁-C₈-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a        C₁-C₈-alkoxycarbonyl, a C₁-C₈-halogenoalkoxycarbonyl having 1 to        5 halogen atoms, a C₁-C₈-alkylcarbonyloxy, a        C₁-C₈-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a        C₁-C₈-alkylsulphenyl, a C₁-C₈-halogenoalkylsulphenyl having 1 to        5 halogen atoms, a C₁-C₈-alkylsulphinyl, a        C₁-C₈-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a        C₁-C₈-alkylsulphonyl, a C₁-C₈-halogenoalkylsulphonyl having 1 to        5 halogen atoms or a C₁-C₈-alkylsulfonamide;

as to the N-oxides of the 2-pyridine thereof;

said process comprising:

(A)-a first step according to reaction scheme 1:

in which:

-   -   A and R² are as defined above; and    -   Hal represents a halogen atom;        comprising the reaction of a halogenobenzoyl derivative with        aqueous R²NH₂, in a R²NH₂ aq./halogenobenzoyl derivative molar        ratio of from 1 to 10, to provide a carboxamide derivative;        (B)-a second step according to reaction scheme 2:

in which R¹, R² and A are as defined above; comprising the reaction of acarboxamide derivative obtained in step one with an aldehyde group in analdehyde group/carboxamide derivative molar ratio of from 1 to 10, in apolar solvent, at a temperature of from 20° C. to reflux, to provide aN-hydroxymethylcarboxamide derivative;

(C)-a third step according to reaction scheme 3:

in which:

-   -   R¹, R² and A are as defined above; and    -   Ac represents an acetyl group;        comprising the reaction of a N-hydroxymethylcarboxamide        derivative obtained in step two with acetic anhydride (Ac₂O) or        acetyl chloride (AcCl) in a Ac₂O or        AcCl/N-hydroxymethylcarboxamide derivative molar ratio of from 1        to 10, in an organic solvent, in the presence of a mineral or        organic base, to provide a N-acetoxymethylcarboxamide        derivative;        (D)-a fourth step according to reaction scheme 4:

in which:

-   -   X, R¹, R², p and A are as defined above;    -   Ac represents an acetyl group;    -   R³ represents a hydrogen atom or CO₂Alk; and    -   Alk represents a C₁-C₈-alkyl group;        comprising the reaction of a N-acetoxymethylcarboxamide        derivative obtained in step three with a 2-pyridyl acetate        derivative in a N-acetoxymethylcarboxamide derivative/2-pyridyl        acetate derivative molar ratio of from 1 to 5, in an organic        solvent, in the presence of a base; to provide a        2-pyridylethylcarboxamide derivative;        (E)-a fifth step comprising the decarboxylation of the        2-pyridylethylcarboxamide derivative obtained in step four into        a compound of general formula (I).

For the purposes of the present invention:

-   -   a halogen atom may be a bromine atom, a chlorine atom, a iodine        atom or a fluorine atom. Preferably, halogen atom means chlorine        atom;    -   carboxy means —C(═O)OH;    -   carbonyl means —C(═O)—;    -   carbamoyl means —C(═O)NH₂;    -   N-hydroxycarbamoyl means —C(═O)NHOH;    -   an alkyl group, an alkenyl group, and an alkynyl group as well        as moieties containing these terms, can be linear or branched;        and    -   a compound used in “catalytic quantity” means that a compound is        used in an amount of 0.01 to 0.2 molar equivalent, preferably        from 0.01 to 0.1 molar equivalent of the respective reagent or        intermediate compound.

During the preparation of compound of general formula (I) according tothe present invention, there is no need to reduce a2-methylcyanopyridine derivative into a 2-ethylaminopyridine derivative,which increases the yield of product obtained by the process accordingto the present invention. Such a process can thus be used at anindustrial scale.

According to the present invention, the 2-pyridyl moiety may besubstituted in any position by (X)_(p), in which X and p are as definedabove. Preferably, the present invention relates to the preparation ofN-[2-(2-pyridinyl)ethyl]carboxamide derivative of general formula (I) inwhich the different characteristics may be chosen alone or incombination as being:

-   -   as regards p, p is 1, 2 or 3. Preferably, p is 2.    -   as regards X, X is chosen, independently of the others, as being        a halogen atom, a C₁-C₈-alkyl or a C₁-C₈-halogenoalkyl having 1        to 5 halogen atoms. More preferably, X is chosen, independently        of the others, as being chlorine or CF₃;    -   as regards the positions in which the 2-pyridyl moiety is        substituted by X, the 2-pyridyl moiety is substituted by X in 3-        and/or in 5-position. Preferably, the 2-pryridyl moiety is        substituted by X in 3- and 5-position.

According to the present invention, the “ethylamide” part of thecompound of formula (I) is substituted by R¹ and R², R¹ and R² being asdefined above. Preferably, the present invention relates to thepreparation of N-[2-(2-pyridinyl)ethyl]benzamide derivative of generalformula (I) in which the different characteristics may be chosen aloneor in combination as being:

-   -   as regards R¹, R¹ is a hydrogen atom, a methyl group, CF₃, CHF₂,        CClF₂ or CCl₃.        More preferably, R¹ is a hydrogen atom;    -   as regards R², R² is a hydrogen atom.

According to the present invention, A may represent a five membered ringnon-fused heterocycle. Specific examples of compounds prepared accordingto the process of the present invention where A is a five memberedheterocycle include compound of general formula (I) wherein:

* A represents a heterocycle of the general formula (A-1)

in which:

-   -   R³ and R⁴ may be the same or different and may be a hydrogen        atom, a halogen atom, an amino group, a nitro group, a        C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl having 1 to 5 halogen        atoms; and    -   R⁵ may be a halogen atom, a nitro group, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-2)

in which:

-   -   R⁶ may be a hydrogen atom, a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms; and    -   R⁷ and R⁸ may be the same or different and may be a hydrogen        atom, a halogen atom, an amino group, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-3)

in which:

-   -   R⁹ may be a halogen atom, a C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms; and    -   R¹⁰ may be a hydrogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-4)

in which:

-   -   R¹¹ and R¹² may be the same or different and may be a hydrogen        atom, a halogen atom, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms, a C₁-C₄-alkylthio, a        C₁-C₄-alkylsulphonyl, a phenyl optionally substituted by a        halogen atom or a C₁-C₄-alkyl or a pyridyl optionally        substituted by a halogen atom or a C₁-C₄-alkyl; and    -   R¹³ may be a halogen atom, a cyano group, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms or a        C₁-C₄-halogenoalkoxy having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-5)

in which:

-   -   R¹⁴ and R¹⁵ may be the same or different and may be a hydrogen        atom, a halogen atom, a C₁-C₄-alkyl, a C₁-C₄-alkyloxy or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms; and    -   R¹⁶ may be a hydrogen atom, a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-6)

in which:

-   -   R¹⁷ may be a hydrogen atom, a halogen atom, a cyano group, a        C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl having 1 to 5 halogen        atoms;    -   R¹⁸ and R²⁰ may be the same or different and may be a hydrogen        atom, a halogen atom, a C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms; and    -   R¹⁹ may be a hydrogen atom, a cyano group, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms, a        C₁-C₄-alkoxy-C₁-C₄-alkyl, a hydroxy-C₁-C₄-alkyl, a        C₁-C₄-alkylsulphonyl, a di(C₁-C₄-alkyl)aminosulphonyl, a        C₁-C₆-alkylcarbonyl, a phenylsulphonyl optionally substituted by        a halogen atom or a C₁-C₄-alkyl, or a benzoyl optionally        substituted by a halogen atom or a C₁-C₄-alkyl.        * A represents a heterocycle of the general formula (A-7)

in which:

-   -   R²¹ may be a hydrogen atom, a cyano group, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms, a        C₁-C₄-alkoxy-C₁-C₄-alkyl, a hydroxy-C₁-C₄-alkyl, a        C₁-C₄-alkylsulphonyl, a di(C₁-C₄-alkyl)aminosulphonyl, a        C₁-C₆-alkylcarbonyl, a phenylsulphonyl optionally substituted by        a halogen atom or a C₁-C₄-alkyl, or a benzoyl optionally        substituted by a halogen atom or a C₁-C₄-alkyl; and    -   R²², R²³ and R²⁴ may be the same or different and may be a        hydrogen atom, a halogen atom, a cyano group, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms or a        C₁-C₄-alkylcarbonyl.        * A represents a heterocycle of the general formula (A-8)

in which:

-   -   R²⁵ may be a hydrogen atom or a C₁-C₄-alkyl; and    -   R²⁶ may be a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-9)

in which:

-   -   R²⁷ may be a hydrogen atom or a C₁-C₄-alkyl; and    -   R²⁸ may be a halogen atom, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms or a phenyl optionally substituted        by a halogen atom or a C₁-C₄-alkyl.        * A represents a heterocycle of the general formula (A-10)

in which:

-   -   R²⁹ may be a hydrogen atom, a halogen atom, an amino group, a        cyano group, a C₁-C₄-alkylamino, a di-(C₁-C₄-alkyl)amino, a        C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms        or a phenyl optionally substituted by a halogen atom or a        C₁-C₄-alkyl; and    -   R³⁰ may be a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-11)

in which:

-   -   R³¹ may be a hydrogen atom, a halogen atom, an amino group, a        cyano group, a C₁-C₄-alkylamino, a di-(C₁-C₄-alkyl)amino, a        C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl having 1 to 5 halogen        atoms; and    -   R³² may be a halogen atom, a C₁-C₄-Alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-12)

in which:

-   -   R³³ may be a halogen atom, a cyano group, a nitro group, a        C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms,        a C₃-C₆-cycloalkyl, a C₁-C₄-alkoxy, a C₁-C₄-halogenoalkoxy        having 1 to 5 halogen atoms, a C₁-C₄-alkylthio, a        C₁-C₄-halogenoalkylthio having 1 to 5 halogen atoms, an        aminocarbonyl group or an aminocarbonyl-C₁-C₄-alkyl;    -   R³⁴ may be a hydrogen atom, a halogen atom, a cyano group, a        nitro group, a C₁-C₄-alkyl, a C₁-C₄-alkoxy or a C₁-C₄-alkylthio;        and    -   R³⁵ may be a hydrogen atom, a phenyl, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms, a        hydroxy-C₁-C₄-alkyl, a C₂-C₆-alkenyl, a C₃-C₆-cycloalkyl, a        C₁-C₄-alkylthio-C₁-C₄-alkyl, a        C₁-C₄-halogenoalkylthio-C₁-C₄-alkyl having 1 to 5 halogen atoms,        a C₁-C₄-alkoxy-C₁-C₄-alkyl or a C₁-C₄-halogenoalkoxy-C₁-C₄-alkyl        having 1 to 5 halogen atoms.        *A represents a heterocycle of the general formula (A-13)

in which:

-   -   R³⁶ may be a hydrogen atom, a halogen atom, a cyano group, a        nitro group, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5        halogen atoms, a C₃-C₆-cycloalkyl, a C₁-C₄-alkoxy, a        C₁-C₄-halogenoalkoxy having 1 to 5 halogen atoms, a        C₁-C₄-alkylthio, a C₁-C₄-halogenoalkylthio having 1 to 5 halogen        atoms, an aminocarbonyl or an aminocarbonyl-C₁-C₄-alkyl;    -   R³⁷ may be a hydrogen atom, a halogen atom, a cyano group, a        C₁-C₄-alkyl, a C₁-C₄-alkoxy, a C₁-C₄-halogenoalkoxy having 1 to        5 halogen atoms or a C₁-C₄-alkylthio; and    -   R³⁸ may be a hydrogen atom, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms, a hydroxy-C₁-C₄-alkyl, a        C₂-C₆-alkenyl, a C₃-C₆-cycloalkyl, a        C₁-C₄-alkylthio-C₁-C₄-alkyl, a        C₁-C₄-halogenoalkylthio-C₁-C₄-alkyl having 1 to 5 halogen atoms,        a C₁-C₄-alkoxy-C₁-C₄-alkyl, a C₁-C₄-halogenoalkoxy-C₁-C₄-alkyl        having 1 to 5 halogen atoms or a phenyl optionally substituted        by a halogen atom, a C₁-C₄-alkyl, a C₁-C₄-alkoxyalkyl or a nitro        group.        * A represents a heterocycle of the general formula (A-14)

in which:

-   -   R³⁹ may be a hydrogen atom, a halogen atom, a cyano group, a        nitro group, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5        halogen atoms, a C₃-C₆-cycloalkyl, a C₁-C₄-alkoxy, a        C₁-C₄-halogenoalkoxy having 1 to 5 halogen atoms, a        C₁-C₄-alkylthio, a C₁-C₄-halogenoalkylthio having 1 to 5 halogen        atoms, an aminocarbonyl, or an aminocarbonyl-C₁-C₄-alkyl;    -   R⁴⁰ may be a hydrogen atom, a halogen atom, a cyano group, a        C₁-C₄-alkyl, a C₁-C₄-alkoxy, a C₁-C₄-alkylthio or a        C₁-C₄-halogenoalky having 1 to 5 halogen atoms;    -   R⁴¹ may be a hydrogen atom, a phenyl, a benzyl, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms, a        hydroxy-C₁-C₄-alkyl, a C₂-C₆-alkenyl, a C₃-C₆-cycloalkyl, a        C₁-C₄-alkylthio-C₁-C₄-alkyl, a        C₁-C₄-halogenoalkylthio-C₁-C₄-alkyl having 1 to 5 halogen atoms,        a C₁-C₄-alkoxy-C₁-C₄-alkyl, a C₁-C₄-halogenoalkoxy-C₁-C₄-alkyl        having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-15)

in which:

-   -   R⁴² may be a hydrogen atom, a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms; and    -   R⁴³ may be a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-16)

in which R⁴⁴ and R⁴⁵ may be the same or different and may be a hydrogenatom, a halogen atom, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5halogen atoms, a phenyl optionally substituted by a halogen atom or aC₁-C₄-alkyl, or a heterocyclyl optionally substituted by a halogen atomor a C₁-C₄-alkyl.

* A represents a heterocycle of the general formula (A-17)

in which

-   -   R⁴⁶ may be a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms. and    -   R⁴⁷ may be a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.        * A represents a heterocycle of the general formula (A-18)

in which R⁴⁸ may be a halogen atom, a C₁-C₄-alkyl or aC₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.

* A represents a heterocycle of the general formula (A-19)

in which:

-   -   R⁴⁹ may be a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms; and    -   R⁵⁰ may be a hydrogen atom, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms, or a phenyl optionally substituted        by a halogen atom or a C₁-C₄-alkyl.        * A represents a heterocycle of the general formula (A-20)

in which R⁵¹ may be a halogen atom, a C₁-C₄-alkyl or aC₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.

According to the present invention, A may also represent a six memberedring non-fused heterocycle. Specific examples of compounds preparedaccording to the process of the present invention where A is a sixmembered heterocycle include

* A represents a heterocycle of the general formula (A-21)

in which:

-   -   R⁵² may be a halogen atom, a hydroxy group, a cyano group, a        C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms,        a C₁-C₄-alkoxy, a C₁-C₄-alkylthio, a C₁-C₄-halogenoalkylthio        having 1 to 5 halogen atoms or a C₁-C₄-halogenoalkoxy having 1        to 5 halogen atoms;    -   R⁵³, R⁵⁴ and R⁵⁵, which may be the same or different, may be a        hydrogen atom, a halogen atom, a cyano group, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms, a C₁-C₄-alkoxy,        a C₁-C₄-alkylthio, a C₁-C₄-halogenoalkoxy having 1 to 5 halogen        atoms, a C₁-C₄-alkylsulphinyl or a C₁-C₄-alkylsulphonyl.        * A represents a heterocycle of the general formula (A-22)

in which:

-   -   R⁵⁶ may be a hydrogen atom, a halogen atom, a hydroxy group, a        cyano group, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5        halogen atoms, a C₁-C₄-alkoxy, a C₁-C₅-alkylthio, a        C₂-C₅-alkenylthio a C₁-C₄-halogenoalkylthio having 1 to 5        halogen atoms, a C₁-C₄-halogenoalkoxy having 1 to 5 halogen        atoms, a phenyloxy optionally substituted by a halogen atom or a        C₁-C₄-alkyl, or a phenylthio optionally substituted by a halogen        atom or a C₁-C₄-alkyl;    -   R⁵⁷, R⁵⁸ and R⁵⁹, which may the same or different, may be a        hydrogen atom, a halogen atom, a cyano group, a C₁-C₄-alkyl, a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms, a C₁-C₄-alkoxy,        a C₁-C₄-alkylthio, a C₁-C₄-halogenoalkoxy having 1 to 5 halogen        atoms, a C₁-C₄-alkylsulphinyl, a C₁-C₄-alkylsulphonyl or a        N-morpholine optionally substituted by a halogen atom or a        C₁-C₄-alkyl, or a thienyl optionally substituted by a halogen        atom or a C₁-C₄-alkyl.        * A represents a heterocycle of the general formula (A-23)

in which R⁶⁰, R⁶¹, R⁶² and R⁶³, which may be the same or different, maybe a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, aC₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms, aC₁-C₄-alkoxy, a C₁-C₄-alkylthio, a C₁-C₄-halogenoalkylthio having 1 to 5halogen atoms, a C₁-C₄-halogenoalkoxy having 1 to 5 halogen atoms, aC₁-C₄-alkylsulphinyl or a C₁-C₄-alkylsulphonyl.

* A represents a heterocycle of the general formula (A-24)

in which:

-   -   R⁶⁴ may be a halogen atom, a C₁-C₄-alkyl or a        C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms;    -   R⁶⁵ may be a hydrogen atom, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms, a C₁-C₆-alkoxycarbonyl, a benzyl        optionally substituted by 1 to 3 halogen atoms, a        benzyloxycarbonyl optionally substituted by 1 to 3 halogen atoms        or a heterocyclyl.        * A represents a heterocycle of the general formula (A-25)

in which:

-   -   R⁶⁶ may be a halogen atom, a hydroxy group, a cyano group, a        C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl having 1 to 5 halogen atoms,        a C₁-C₄-alkoxy, a C₁-C₄-alkylthio, a C₁-C₄-halogenoalkylthio        having 1 to 5 halogen atoms or a C₁-C₄-halogenoalkoxy having 1        to 5 halogen atoms;    -   R⁶⁷ may be a hydrogen atom, a C₁-C₄-alkyl, a C₁-C₄-halogenoalkyl        having 1 to 5 halogen atoms or a benzyl.        * A represents a heterocycle of the general formula (A-26)

in which:

-   -   X¹ may be a sulphur atom, —SO—, —SO₂— or —CH₂—;    -   R⁶⁸ may be a C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl having 1 to 5        halogen atoms; and    -   R⁶⁹ and R⁷⁰ may be the same or different and may be a hydrogen        atom or a C₁-C₄-alkyl.        * A represents a heterocycle of the general formula (A-27)

in which:

-   -   R⁷¹ may be a C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl having 1 to 5        halogen atoms;        * A represents a heterocycle of the general formula (A-28)

in which:

-   -   R⁷² may be a C₁-C₄-alkyl or a C₁-C₄-halogenoalkyl having 1 to 5        halogen atoms.        * A represents a heterocycle of the general formula (A-29)

in which R⁷³ may be a halogen atom, a C₁-C₄-alkyl or aC₁-C₄-halogenoalkyl having 1 to 5 halogen atoms.

According to the present invention, A may also represent an optionallysubstituted phenyl group. Preferably, the present invention relates tothe preparation of N-[2-(2-pyridinyl)ethyl]carboxamide derivative ofgeneral formula (I) in which A is a phenyl group and in which thedifferent characteristics may be chosen alone or in combination asbeing:

-   -   A is substituted by 1 or 2 substituents. More preferably, A is        substituted by 1 substituent.    -   each substituent is chosen, independently of the others, as        being a hydrogen atom, a halogen atom, a C₁-C₈-alkyl or a        C₁-C₈-halogenoalkyl having 1 to 5 halogen atoms. More preferably        each substituent is chosen, independently of the others, as        being chlorine or CF₃;    -   the phenyl moiety is substituted in ortho position.

The process of the present invention is particularly suitable for thepreparation of:

-   -   N-{2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-2-trifluoromethylbenzamide;    -   N-{2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-2-iodobenzamide;        or    -   N-{2-[3,5-dichloro-2-pyridinyl]ethyl}-2-trifluoromethylbenzamide.

The first step (step A) of the process according to the presentinvention comprises the reaction of a halogenobenzoyl derivative withaqueous R²NH₂, in a R²NH₂ aq./halogenobenzoyl derivative molar ratio offrom 1 to 10, to provide a carboxamide derivative. Preferably, the R²NH₂aq./halogenobenzoyl derivative molar ratio of from 1 to 5.

Step A does not necessarily require the use of a solvent. Preferably,step A is conducted in the presence of a solvent. More preferably, thesolvent is chosen as being a mixture of water and of an organic solvent.Suitable organic solvent includes tetrahydrofuran (THF) or toluene.

Step A does not necessarily require specific temperature conditions.Preferably, step A is conducted at a temperature of from 0° C. toreflux. More preferably, step A is conducted at a temperature of from20° C. to reflux. Even more preferably step A is conducted at atemperature of from 60° C. to reflux.

The second step (step B) of the process according to the presentinvention comprises the reaction of a carboxamide derivative obtained instep A with an aldehyde group in an aldehyde group/carboxamidederivative molar ratio of from 1 to 10, in a polar solvent, at atemperature of from 20° C. to reflux, to provide aN-hydroxymethylcarboxamide derivative. Preferably, step B may beconducted in the following conditions, chosen alone or in combination:

-   -   the acyl group/carboxamide derivative molar ratio is of from 1        to 5;    -   the polar solvent is chosen as being water or an alcohol;    -   the reaction is conducted at reflux.

Step B is not necessarily conducted in the presence of a base.Preferably, step B is conducted in the presence of a mineral base incatalytic quantity. More preferably, the mineral base is chosen as beingK₂CO₃, Na₂CO₃ or KOH.

The third step (step C) of the process according to the presentinvention comprises the reaction of a N-hydroxymethylcarboxamidederivative obtained in step B with Ac₂O or AcCl in a Ac₂O orAcCl/N-hydroxymethylcarboxamide derivative molar ratio of from 1 to 10,in an organic solvent, in the presence of a mineral or organic base, toprovide a N-acetoxymethylcarboxamide derivative. Preferably, step C maybe conducted in the following conditions, chosen alone or incombination:

-   -   the Ac₂O or AcCl/N-hydroxymethylcarboxamide derivative molar        ratio of from 1 to 5, more preferably of 1;    -   the reaction is conducted with Ac₂O;    -   the mineral base is chosen as being Na₂CO₃, Li₂CO₃, K₂CO₃,        LiOAc, NaOAc or KOAc. More preferably, the mineral base is        chosen as being Na₂CO₃ or NaOAc;    -   the organic base is chosen as being NEt₃ or        N,N-dimethylaminopyridine, diazabicyclooctane (DABCO). More        preferably, the organic base is chosen as being        N,N-dimethylaminopyridine, diazabicyclooctane (DABCO);    -   Ac₂O or AcCl is introduced in stoechiometric quantity;    -   the base is introduced in stoechiometric quantity or in        catalytic quantity. More preferably, the base is introduced in        catalytic quantity.

Step C does not necessarily require specific temperature condition.Preferably, step C is conducted at a temperature of from 0° C. to 50°C., more preferably at a temperature of from 5° C. to 35° C., even morepreferably at room temperature.

The fourth step (step D) of the process according to the presentinvention comprises the reaction of a N-acetoxymethylcarboxamidederivative obtained in step C with a 2-pyridyl acetate derivative in aN-acetoxymethylcarboxamide derivative/2-pyridyl acetate derivative molarratio of from 1 to 5, in an organic solvent, in the presence of a base,to provide a 2-pyridylethylcarboxamide derivative. Preferably, step Dmay be conducted in the following conditions, chosen alone or incombination:

-   -   the N-acetoxymethylcarboxamide derivative/2-pyridyl acetate        derivative molar ratio is of 1;    -   the base is chosen as being a alkaline earth metal base, a        alkali metal hydride base, a hydroxide base, an amide base, an        alcoholate base, an acetate base, a carbonate base, a hydrogen        carbonate base or a tertiary amine base. More preferably, the        base is chosen as being hydrogen carbonate base which includes        sodium hydride, sodium amide, lithium diisoproylamide, sodium        methanolate, sodium ethanolate, potassium tert-butanolate,        sodium acetate, potassium acetate, calcium acetate, sodium        hydroxide, potassium hydroxide, sodium carbonate, potassium        carbonate, potassium bicarbonate, sodium bicarbonate, ammonium        carbonate, trimethylamine, triethylamine, tributyl-amine,        N,N-dimethyl-aniline, N,N-di-methyl-benzylamine pyridine,        N-methylpiperidine, N-methyl-morpholine,        N,N-dimethylaminopyridine, diazabicyclooctane (DABCO),        diazabicyclononene (DBN) or diazabicycloundecene (DBU). Even        more preferably, the base is chosen as being sodium hydride,        sodium hydroxide, sodium acetate, potassium carbonate, potassium        hydroxide, triethylamine or potassium tert-butanolate;    -   the organic solvent is chosen as being an aliphatic solvent, an        alicyclic solvent, an aromatic hydrocarbon solvent, a        halogenated hydrocarbon solvent, an ether solvent, an amide        solvent or an urea solvent. More preferably, the organic solvent        is chosen as being petroleum ether, hexane, heptane,        cyclo-hexane, methyl-cyclohexane, benzene, toluene, xylene,        decalin, chloro-benzene, dichloro-benzene, trifluoromethyl        benzene, dichloromethane, chloroform, carbon tetra-chloride,        di-chloroethane, tri-chloro-ethane, diethyl ether, diisopropyl        ether, methyl tert-butyl-ether, methyl tert-amyl-ether, dioxane,        tetrahydrofuran, 1,2-di-methoxyethane, 1,2-di-ethoxy-ethane,        anisole, N,N-dime-thyl-formamide, N,N-dimethyl-acetamide,        N-methyl-formanilide, N-methyl-pyrrolidone,        hexamethyl-phosphoric-triamide or 1,3-dimethyl-2-2-imidazolinone        or N,N-dimethyl acetamide (DMAC). Even more preferably, the        organic solvent is chosen as being tetrahydrofuran (THF) or        N,N-dimethyl acetamide (DMAC).

Step D does not necessarily require specific temperature condition.Preferably, step D is conducted at a temperature of from 0° C. to 80°C., more preferably at a temperature of from 5° C. to 50° C.

The fifth step (step E) of the process according to the presentinvention comprises the decarboxylation of the 2-pyridylethylcarboxamidederivative obtained in step D into a compound of general formula (I) asdefined above. Such a decarboxylation reaction may be performed by knownmethods. Such a decarboxylation reaction may for example be conductedaccording to the Krapcho reaction described in A.P. Synthesis, 1982,805, 893, herein incorporated by reference.

The compound of general formula (I) according to the present inventioncan be prepared according to the above described process. It willnevertheless be understood that, on the basis of his general knowledgeand of available publications, the skilled worker will be able to adaptthis method according to the specifics of each of the compounds, whichit is desired to synthesise.

Certain of the intermediates used for the preparation of compound ofgeneral formula (I) are novel. Therefore, the present invention alsorelates to novel intermediate compounds useful for the preparation ofcompound of general formula (I). Thus, according to the presentinvention, there is provided a compound of general formula (II)

in which:

-   -   R¹, R² and A are as defined above; and    -   Ac represents an acetyl group.

According to the present invention, there is also provided a compound ofgeneral formula (III)

in which:

-   -   X, R¹, R², R³, p and A are as defined above; and    -   Alk represents a C₁-C₈-alkyl group.

The present invention will now be illustrated with reference to thefollowing examples.

Preparation ofN-{2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-2-trifluoromethylbenzamide

Step 1: Preparation of a 2-trifluoromethylbenzamide

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with2-trifluoromethylbenzoic acid chloride (5.6 g, 26.9 mmol) andtetrahydrofuran (20 ml). An aqueous solution of ammonia 20% (20 ml,107.6 mmol) was added at 20° C. during 15 min. The reaction mixture wasagitated for two hours. The aqueous phase was then extracted 4 timeswith dichloromethane (4×50 ml), the organic phases were combined, driedover MgSO₄ and concentrated to the dryness under vacuum.

4.43 g of a white solid were obtained (isolated yield=87%).

NMR¹H(CDCl₃, 300 MHz): 5.6-6.2 (br, 2H, NH₂); 7.5-7.8 (m, 4H, Haro)

Step 2: Preparation of a N-hydroxymethyl 2-trifluoromethylbenzamide

A two-necked round bottom flask equipped with a magnetic bar, athermometer and a reflux condenser was charged with2-trifluoromethylbenzamide (5.59 g, 29.6 mmol), water (35 ml), K₂CO₃(0.118 g, 0.855 mmol) and formaldehyde (3.82 g, 127.3 mmol). Thereaction mixture was heated at 100° C. for 15 hours. The aqueous phasewas extracted 4 times with AcOEt (4×200 ml) at room temperature, theorganic phases were mixed, dried over MgSO₄ and concentrated to thedryness under vacuum.

5.8 g of a white solid were obtained (isolated yield=90%).

NMR¹H(CDCl₃, 300 MHz): 3.7 (t, 1H); 4.9 (t, 2H, CH₂); 6.8 (s, 1H);7.5-7.7 (m, 4H, Haro).

Mass spectrum: [M+1]=220.

Step 3: Preparation of a N-acetoxymethyl 2-trifluoromethylbenzamide

EXAMPLE 1

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (3 g, 13.7 mmol), CH₂Cl₂ (20 ml) and NEt₃(1.93 ml, 13.7 mmol). The solution was cold to 5° C. and the Ac₂O (1.93ml, 13.7 mmol) was slowly added. The reaction mixture was agitated fortwo hours at 5° C. and 1 h at 20° C. The reaction mixture was washedwith water, dried over MgSO₄ and concentrated to the dryness undervacuum.

3.5 g of a white solid were obtained (isolated yield=80%).

NMR¹H(CDCl₃, 300 MHz): 2.1 (s, 3H, CH₃); 5.4 (d, 2H, CH₂); 7.0 (s, 1H);7.5-7.7 (m, 4H, Haro).

EXAMPLE 2

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), MeCN (30 ml) and K₂CO₃(5.53 g, 40 mmol). The solution was cold to 5° C. and the Ac2O (2.35 g,23 mmol) was slowly added. The reaction mixture was agitated for 6 hoursat 5° C. The reaction mixture was filtrated, the residue washed with asmall amount of MeCN, and the filtrate concentrated to dryness undervacuum.

5 g of a white solid were obtained.

Purity (HPLC): 89.9%, giving an isolated yield of 86%.

Mass spectrum: [M+1]=262, base peak=202[M+1−AcOH].

EXAMPLE 3

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), MeCN (30 ml), K₂CO₃ (2.76g, 20 mmol), and NEt₃ (0.2 g, 2 mmol). The solution was cooled to 5° C.and the Ac2O (2.35 g, 23 mmol) was slowly added. The reaction mixturewas agitated for 2 hours at 5° C. and 3 hours at room temperature. Thereaction mixture was filtrated, the residue washed with a small amountof MeCN, and the filtrate concentrated to dryness under vacuum.

5.38 g of a white solid were obtained. 0.32 g had to be substracted dueto 2 mmol of NEt₃xAcOH, giving 5.06 g.

Purity (HPLC): 93.3%, giving an isolated yield of 90%.

EXAMPLE 4

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), MeCN (30 ml), K₂CO₃ (2.76g, 20 mmol), and DABCO (1,4-diazabicyclo[2.2.2]octane) (0.224 g, 2mmol). The solution was coold to 5° C. and the Ac2O (2.35 g, 23 mmol)was slowly added. The reaction mixture was agitated for 2 hours at 5° C.and 3 hours at room temperature. The reaction mixture was filtrated, theresidue washed with a small amount of MeCN, and the filtrateconcentrated to dryness under vacuum.

5.57 g of a white solid were obtained. 0.46 g had to be substracted dueto 2 mmol of DABCOx2AcOH, giving 5.11 g.

Purity (HPLC): 92.8%, giving an isolated yield of 91%.

EXAMPLE 5

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and Na₂CO₃(2.12 g, 20 mmol). The Ac2O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH2Cl2 and the organic phase washed withwater. The organic phase was dried over MgSO4 and concentrated undervacuum. and the filtrate concentrated under vacuum. 5.8 g of acolourless oil were obtained. Purity (HPLC): 53.75% (34.6% of DMAC),giving an isolated yield of 60%.

EXAMPLE 6

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and Li₂CO₃(1.478 g, 20 mmol). The Ac2O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH2Cl2 and the organic phase washed withwater. The organic phase was dried over MgSO4 and concentrated undervacuum. and the filtrate concentrated under vacuum.

6.2 g of a colourless oil were obtained.

Purity (HPLC): 56% (18.9% of DMAC), giving an isolated yield of 66.5%.

EXAMPLE 7

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and Na₂CO₃(1.06 g, 10 mmol). The Ac2O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH2Cl2 and the organic phase washed withwater. The organic phase was dried over MgSO4 and concentrated undervacuum. and the filtrate concentrated under vacuum.

5.45 g of a colourless oil were obtained.

Purity (HPLC): 85.45% (10.7% of DMAC) giving an isolated yield of 89%.

EXAMPLE 8

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and Na₂CO₃(0.53 g, 5 mmol). The Ac2O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH2Cl2 and the organic phase washed withwater. The organic phase was dried over MgSO4 and concentrated undervacuum. and the filtrate concentrated under vacuum.

6.2 g of a colourless oil were obtained.

Purity (HPLC): 81.5% (15% of DMAC), giving an isolated yield of 97%.

EXAMPLE 9

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and Na₂CO₃(0.265 g, 2.5 mmol). The Ac2O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH2Cl2 and the organic phase washed withwater. The organic phase was dried over MgSO4 and concentrated undervacuum. and the filtrate concentrated under vacuum.

6.6 g of a colourless oil were obtained.

Purity (HPLC): 63% (30.8% of DMAC), giving an isolated yield of 80%.

EXAMPLE 10

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and K₂CO₃(0.691 g, 5 mmol). The Ac2O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH2Cl2 and the organic phase washed withwater. The organic phase was dried over MgSO4 and concentrated undervacuum. and the filtrate concentrated under vacuum.

6.55 g of a colourless oil were obtained.

Purity (HPLC): 63% (30.6% of DMAC), giving an isolated yield of 79%.

EXAMPLE 11

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and NaOAc(1.641 g, 20 mmol). The Ac₂O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH₂Cl₂, and the organic phase washedwith water. The organic phase was dried over MgSO₄ and the filtrateconcentrated under vacuum.

6 g of a colourless oil were obtained.

Purity (HPLC): 84.9% (8% of DMAC), giving an isolated yield of 97.5%.

EXAMPLE 12

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with N-hydroxymethyl2-trifluoromethylbenzamide (4.38 g, 20 mmol), DMAC (30 ml) and NaOAc(0.41 g, 5 mmol). The Ac₂O (2.35 g, 23 mmol) was slowly added at roomtemperature. The reaction mixture was agitated for 4 hours at roomtemperature. Then the reaction mixture was filtrated and the residuewashed with a small amount of DMAC. To the filtrate was added water.This mixture was extracted with CH₂Cl₂, and the organic phase washedwith water. The organic phase was dried over MgSO₄ and the filtrateconcentrated under vacuum.

6.1 g of a colourless oil were obtained.

Purity (HPLC): 85.3% (6.7% of DMAC), giving an isolated yield of 99.6%.

The purified product shows a melting point of 58-59° C.

Step 4: Preparation of a 3-chloro 5-trifluoromethyl 2-pyridylethyl(diethyl ester)2-trifluoromethylbenzamide

Preparation of a 3-chloro 5-trifluoromethyl 2-pyridyl malonic acid ethylester EXAMPLE 1

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with 2,3-dichloro5-trifluoromethylpyridyl (2.67 g, 12.4 mmol), NMP (20 ml) and NaOH (1.19g, 31 mmol). Diethyl malonate (2.39 g, 14.8 mmol) was slowly added at20° C. The reaction mixture was agitated for 20 hours. The reactionmixture was diluted with CH₂Cl₂ and washed with water. The organic phasewas dried over MgSO₄ and concentrated to the dryness under vacuum.

3.57 g of a white solid were obtained (isolated yield=85%).

Mass spectrum: [M+1]=339.

EXAMPLE 2

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with 2,3-dichloro5-trifluoromethyl pyridine (5.4 g, 25 mmol), DMAC (20 ml) and NaOH (2.4g, 40 mmol). Diethyl malonate (4.8 g, 30 mmol) was slowly added at 20°C. The temperature was raised to 70° C. and the reaction mixture wasagitated for 3 hours at 70° C. Then the reaction mixture was cooled toroom temperature and mixed with 200 ml of water. This mixture wasextracted with CH2Cl2 and the organic phase washed with water. Theorganic phase was dried over MgSO4 and concentrated under vacuum.

9.66 g of an orange oil were obtained.

Purity (GC): 78.7% (16.3% DMAC), giving an isolated yield of about 89%.

Mass spectrum: [M+1]=340 (³⁵Cl)

Boiling point=87-90° C./0.06-0.07 mbar.

Melting point: 45.5-47° C. (cyclohexane).

NMR¹H(CDCl₃, 400 MHz): 1.30 (t, 6H, 2CH₃); 4.31 (m, 4H, 2CH₂); 5.25 (s,1H, CH); 7.96 (d, 1H, Haro); 8.76 (d, 1H, Haro).

Preparation of a 3-chloro 5-trifluoromethyl 2-pyridyl ethyl (diethylester) 2-trifluoromethylbenzamide EXAMPLE 1

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with NaH (60% oil, 0.06g, 1.47 mmol) and THF (10 ml). A solution of 3-chloro 5-trifluoromethyl2-pyridyl malonic acid ethyl ester (0.321 g, 1.23 mmol) and Nacetoxymethyl 2-trifluoromethylbenzamide (0.418 g, 1.23 mmol) in THF wasadded slowly. at 20° C. The reaction mixture was agitated for 1 hours.Water was slowly added and the aqueous phase was extracted with CH2Cl2.The organic phases were combined, dried over MgSO₄ and concentrated tothe dryness under vacuum.

0.78 g of a white solid was obtained (isolated yield=88%).

NMR¹H(CDCl₃, 300 MHz): 1.3 (t, 6H, 2CH₃); 4.3 (m, 4H, 2CH₂); 4.6 (d, 2H,CH₂); 6.9 (t, 1H, CH); 7.4-7.6 (m, 4H, Haro); 8.0 (s, 1H, Haro); 8.6 (s,1H, Haro).

Mass spectrum: [M+1]=541.

EXAMPLE 2

A round bottom flask equipped with a magnetic bar and a thermometer wascharged with NaOH (0.24 g, 6 mmol), DMAC (10 ml), 3-chloro5-trifluoromethyl 2-pyridyl malonic acid ethyl ester (1.67 g, 5 mmol)and N-acetoxymethyl 2-trifluoromethylbenzamide (1.31 g, 5 mmol). Thereaction mixture was heated to 90° C. and agitated for 3 hours at thistemperature. Then the mixture was cooled to room temperature. Water wasslowly added and the aqueous phase was extracted with CH2Cl2. Theorganic phases were combined, dried over MgSO4 and concentrated to thedryness under vacuum.

2.74 g were obtained.

Purity (HPLC): 94.3%, giving an isolated yield of 95.5%.

Melting point: 76-80° C.

EXAMPLE 3

A round bottom flask equipped with a magnetic bar and a thermometer wascharged with NaOH (0.04 g, 1 mmol), DMAC (10 ml), 3-chloro5-trifluoromethyl 2-pyridyl malonic acid ethyl ester (1.67 g, 5 mmol)and N-acetoxymethyl 2-trifluoromethylbenzamide (1.31 g, 5 mmol). Thereaction mixture was heated to 70° C. and agitated for 5 hours at thistemperature. Then the mixture was cooled to room temperature. Water wasslowly added and the aqueous phase was extracted with CH2Cl2. Theorganic phases were combined, dried over MgSO4 and concentrated to thedryness under vacuum.

2.88 g were obtained.

Purity (HPLC): 82.2%, giving an isolated yield of 87.5%.

EXAMPLE 4

A round bottom flask equipped with a magnetic bar and a thermometer wascharged with NaOAc (0.41 g, 5 mmol), DMAC (10 ml), 3-chloro5-trifluoromethyl 2-pyridyl malonic acid ethyl ester (1.67 g, 5 mmol)and N-acetoxymethyl 2-trifluoromethylbenzamide (1.31 g, 5 mmol). Thereaction mixture was heated to 70° C. and agitated for 5 hours at thistemperature. Then the mixture was cooled to room temperature. Water wasslowly added and the aqueous phase was extracted with CH2Cl2. Theorganic phases were combined, dried over MgSO4 and concentrated to thedryness under vacuum.

2.76 g were obtained.

Purity (HPLC): 86.9%, giving an isolated yield of 88.7%.

Step 4: Preparation of a 3-chloro 5-trifluoromethyl 2-pyridylethyl(dimethyl ester) 2-trifluoromethylbenzamide

Preparation of a 3-chloro 5-trifluoromethyl 2-pyridyl malonic acidmethyl ester

A two-necked round bottom flask equipped with a magnetic bar, athermometer and an addition funnel was charged with DMAC (200 ml) andNaOH (12 g, 300 mmol). Then dimethyl malonate (20.4 g, 150 mmol) wasadded at a temperature of 65-70° C. After that 2,3-dichloro5-trifluoromethylpyridine (27 g, 125 mmol) was added slowly at the sametemperature. The temperature was raised to 90° C., and the reactionmixture was agitated for 1 hour at 90° C. The reaction mixture wascooled to room temperature and mixed with 250 ml of water. This mixturewas extracted with CH2Cl2 and the organic phase washed with water. Theorganic phase was dried over MgSO4 and concentrated under vacuum.

39.2 g of an orange oil were obtained.

Purity (GC): 88.65% (5.8% DMAC), giving an isolated yield of about 89%.

Mass spectrum (GC/MS): 311 (M⁺, ³⁵Cl); 276 (M—Cl, base peak).

NMR¹H(CDCl₃, 400 MHz): 3.83 (s, 6H, 2CH₃); 5.30 (s, 1H, CH); 7.97 (1H,Haro); 8.76 (d, 1H, Haro).

Boiling point: 91-94° C./0.18 mbar

Melting point: 49.5-50.5° C. (cyclohexane).

Preparation of a 3-chloro 5-trifluoromethyl 2-pyridyl ethyl(dimethylester) 2-trifluoromethylbenzamide

A round bottom flask equipped with a magnetic bar and a thermometer wascharged with NaOH (0.24 g, 6 mmol), DMAC (10 ml), 3-chloro5-trifluoromethyl 2-pyridyl malonic acid methyl ester (1.56 g, 5 mmol)and N-acetoxymethyl 2-trifluoromethylbenzamide (1.31 g, 5 mmol). Thereaction mixture was heated to 90° C. and agitated for 2 hours at thistemperature. Then the mixture was cooled to room temperature. Water wasslowly added and the aqueous phase was extracted with CH2Cl2. Theorganic phases were combined, dried over MgSO4 and concentrated to thedryness under vacuum.

2.5 g were obtained.

Purity (HPLC): 84.1%, giving an isolated yield of 82%.

Mass spectrum: [M+1]=513 (³⁵Cl).

Mass spectrum (GC/MS)=512 (M⁺, ³⁵Cl), 173 (base peak).

Step 5: Preparation of aN-{2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-2-trifluoromethylbenzamide

A two-necked round bottom flask equipped with a magnetic bar, athermometer and a reflux condenser was charged with 3-chloro5-trifluoromethyl 2-pyridyl ethyl (diethylester)2-trifluoromethylbenzamide (0.610 g, 1.13 mmol), KCl (0.028 g, 0.37mmol), HCl aq. 32% (0.17 ml, 1.5 mmol) and NMP (15 ml). The reactionmixture was heated at 180° C. 24 hours. At 20° C., water was added andthe aqueous phase was extracted three times with CH₂Cl₂. The organicphases were combined, dried over MgSO₄ and concentrated to the drynessunder vacuum.

0.5 g of a yellow solid was obtained (isolated yield=66%).

Mass spectrum: [M+1]=396.

1. A process for the preparation of aN-[2-(2-pyridinyl)ethyl]carboxamide derivative of formula (I) or a saltthereof

in which: p is an integer equal to 1, 2, 3 or 4; X is the same ordifferent and is a hydrogen atom, a halogen atom, a nitro group, a cyanogroup, a hydroxy group, an amino group, a sulfanyl group, apentafluoro-λ⁶-sulfanyl group, a formyl group, a formyloxy group, aformylamino group, a carboxy group, a carbamoyl group, aN-hydroxycarbamoyl group, a carbamate group, a(hydroxyimino)-C₁-C₆-alkyl group, a C₁-C₈-alkyl, a C₁-C₈-halogenoalkylhaving 1 to 5 halogen atoms, a C₂-C₈-alkenyl, a C₂-C₈-alkynyl, aC₁-C₈-alkylamino, a di-C₁-C₈-alkylamino, a C₁-C₈-alkoxy, aC₁-C₈-halogenoalkoxy having 1 to 5 halogen atoms, a C₁-C₈-alkylsulfanyl,a C₁-C₈-halogenoalkylsulfanyl having 1 to 5 halogen atoms, aC₂-C₈-alkenyloxy, a C₂-C₈-halogenoalkenyloxy having 1 to 5 halogenatoms, a C₃-C₈-alkynyloxy, a C₃-C₈-halogenoalkynyloxy having 1 to 5halogen atoms, a C₃-C₈-cycloalkyl, a C₃-C₈-halogenocycloalkyl having 1to 5 halogen atoms, a C₁-C₈-alkylcarbonyl, a C₁-C₈-halogenoalkylcarbonylhaving 1 to 5 halogen atoms, a C₁-C₈-alkylcarbamoyl, adi-C₁-C₈-alkylcarbamoyl, a (N—C₁-C₈-alkyl)oxycarbamoyl, aC₁-C₈-alkoxycarbamoyl, a (N—C₁-C₈-alkyl)-C₁-C₈-alkoxycarbamoyl, aC₁-C₈-alkoxycarbonyl, a C₁-C₈-halogenoalkoxycarbonyl having 1 to 5halogen atoms, a C₁-C₈-alkylcarbonyloxy, aC₁-C₈-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, aC₁-C₈-alkylcarbonylamino, a C₁-C₈-halogenoalkylcarbonylamino having 1 to5 halogen atoms, a C₁-C₈-alkylaminocarbonyloxy, adi-C₁-C₈-alkylaminocarbonyloxy, a C₁-C₈-alkyloxycarbonyloxy, aC₁-C₈-alkylsulphenyl, a C₁-C₈-halogenoalkylsulphenyl having 1 to 5halogen atoms, a C₁-C₈-alkylsulphinyl, a C₁-C₈-halogenoalkylsulphinylhaving 1 to 5 halogen atoms, a C₁-C₈-alkylsulphonyl, aC₁-C₈-halogenoalkyl-sulphonyl having 1 to 5 halogen atoms, a(C₁-C₆-alkoxyimino)-C₁-C₆-alkyl, a (C₁-C₆-alkenyloxyimino)-C₁-C₆-alkyl,a (C₁-C₆-alkynyloxyimino)-C₁-C₆-alkyl, a (benzyloxyimino)-C₁-C₆-alkyl, abenzyloxy, a benzylsulfanyl, a benzylamino, a phenoxy, a phenylsulfanylor a phenylamino; R¹ is selected from the group consisting of a hydrogenatom, a C₁-C₈-alkyl, a C₁-C₈-halogenoalkyl having 1 to 5 halogen atomsand a C₁-C₈-alkoxycarbonyl; R² is selected from the group consisting ofa hydrogen atom and a cyclopropyl group; and A represents a phenyl groupor a 5-, 6- or 7-membered non-fused heterocycle with one, two or threeheteroatoms which may be the same or different, the heterocycle beinglinked by a carbon atom; each of this group being optionally substitutedby one or more substituents independently selected from the groupconsisting of a halogen atom, a nitro group, a cyano group, a hydroxygroup, an amino group, a sulfanyl group, a pentafluoro-λ⁶-sulfanylgroup, a formyl group, a formyloxy group, a formylamino group, a carboxygroup, a C₁-C₈-alkyl, a C₁-C₈-halogenoalkyl having 1 to 5 halogen atoms,a C₂-C₈-alkenyl, a C₂-C₈-alkynyl, a C₁-C₈-alkylamino, adi-C₁-C₈-alkylamino, a C₁-C₉-alkoxy, a C₁-C₈-halogenoalkoxy having 1 to5 halogen atoms, a C₁-C₈-alkoxy-C₂-C₈-alkenyl, a C₁-C₈-alkylsulfanyl, aC₁-C₈-halogenoalkylsulfanyl having 1 to 5 halogen atoms, aC₁-C₈-alkoxycarbonyl, a C₁-C₈-halogenoalkoxycarbonyl having 1 to 5halogen atoms, a C₁-C₈-alkylcarbonyloxy, aC₁-C₈-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, aC₁-C₈-alkylsulphenyl, a C₁-C₈-halogenoalkylsulphenyl having 1 to 5halogen atoms, a C₁-C₈-alkylsulphinyl, a C₁-C₈-halogenoalkylsulphinylhaving 1 to 5 halogen atoms, a C₁-C₈-alkylsulphonyl, aC₁-C₈-halogenoalkylsulphonyl having 1 to 5 halogen atoms and aC₁-C₈-alkylsulfonamide; and the N-oxide of the 2-pyridine thereof; saidprocess comprising: (A)-a first step according to reaction scheme 1:

in which: A and R² are as defined above; and Hal represents a halogenatom; comprising the reaction of a halogenobenzoyl derivative withaqueous R²NH₂, in a R²NH₂ aq./halogenobenzoyl derivative molar ratio offrom 1 to 10, to provide a carboxamide derivative; (B)-a second stepaccording to reaction scheme 2:

in which: R¹, R² and A are as defined above; comprising the reaction ofa carboxamide derivative obtained in step one with an aldehyde group inan aldehyde group/carboxamide derivative molar ratio of from 1 to 10, ina polar solvent, at a temperature of from 20° C. to reflux, to provide aN-hydroxymethylcarboxamide derivative; (C)-a third step according toreaction scheme 3:

in which: R¹, R² and A are as defined above; and Ac represents an acetylgroup; comprising the reaction of a N-hydroxymethylcarboxamidederivative obtained in step two with acetic anhydride (Ac₂O) or acetylchloride (AcCl) in an Ac₂O or AcCl/N-hydroxymethylcarboxamide derivativemolar ratio of from 1 to 10, in an organic solvent, in the presence of amineral or organic base, to provide a N-acetoxymethylcarboxamidederivative; (D)-a fourth step according to reaction scheme 4:

in which: X, R¹, R², p and A are as defined above; Ac represents anacetyl group; R³ represents a hydrogen atom or CO₂Alk; and Alkrepresents a C₁-C₈-alkyl group; comprising the reaction of aN-acetoxymethylcarboxamide derivative obtained in step three with a2-pyridyl acetate derivative in a N-acetoxymethylcarboxamidederivative/2-pyridyl acetate derivative molar ratio of from 1 to 5, inan organic solvent, in the presence of a base; to provide a2-pyridylethylcarboxamide derivative; and (E)-a fifth step comprisingthe decarboxylation of the 2-pyridylethylcarboxamide derivative obtainedin step four into a compound of formula (I).
 2. The process of claim 1wherein p is
 2. 3. The process of claim 1 wherein X is independentlyselected from the group consisting of chlorine and CF₃.
 4. The processof claim 1 wherein the 2-pyridyl moiety is substituted by X in the 3-and/or in the 5-position.
 5. The process of claim 1 wherein R¹ isselected from the group consisting of a hydrogen atom, a methyl group,CF₃, CHF₂, CClF₂ and CCl₃.
 6. The process of claim 1 wherein R² is ahydrogen atom.
 7. The process of claim 1 wherein A is a phenyl group. 8.The process of claim 7 wherein A is substituted by one or twosubstituents.
 9. The process of claim 8 wherein each substituent of A isindependently selected from the group consisting of chlorine and CF₃.10. The process of claim 7 wherein the A is substituted in orthoposition.
 11. The process of claim 1 wherein the compound of formula (I)is selected from the group consisting of:N-{2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-2-trifluoromethylbenzamide;N-{2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-2-iodobenzamide;and N-{2-[3,5-dichloro-2-pyridinyl]ethyl}-2-trifluoromethylbenzamide.12. The process of claim 1 wherein step A is conducted in the presenceof a mixture of water and an organic solvent.
 13. The process of claim 1wherein step A is conducted at a temperature of from 0° C. to reflux.14. The process of claim 1 wherein step B is conducted in the presenceof a mineral base in catalytic quantity.
 15. The process of claim 1wherein step C is conducted at a temperature of from 0° C. to 50° C. 16.The process of claim 1 wherein, in step C, the base is introduced incatalytic quantity.
 17. The process according to claim 1 wherein step Dis conducted at a temperature of from 0° C. to 80° C.